1. Technical Field
This disclosure is generally directed to diaphragm technologies for microvalves, micropumps and other pneumatic fluidic elements for use in microassay devices, and to their methods of manufacture.
2. Description of the Related Art
Microassay cartridges have found increasing use as devices for diagnostic assays. The devices described by Wilding in U.S. Pat. No. 5,304,487 consisted of “mesoscale” channels and chambers formed on reusable silicon substrates that were infused with fluid reagents from off-cartridge syringe pumps. Little consideration was given to on-board fluid handling and control. However, practical commercial applications have led in the direction of “consumable” cartridges—disposable, single use “sample-to-answer” cartridges that are self-contained for all reagents needed for a particular assay or panel of assays.
Microscale means for handling fluids include mechanical hydraulic systems such as piston driven devices, electrical hydraulic systems such as electrokinetic pump and valve devices, and pneumohydraulic systems. Of these, those systems with pneumatic actuators and control surfaces have proven to be particularly practical in controlling microscale fluid flows.
One well known class of fluidic devices having a pneumatic interface is manufactured by the Assignee, Micronics, Inc. (Redmond, Wash.). Control of fluid flow in microfluidic channels is achieved with a MICROFLOW® system pneumatic controller that operates miniature valves in a plastic cartridge according to programmable valve logic. Diaphragms separate the pneumatic side and the hydraulic side of the cartridges; i.e., the valve diaphragms are interface elements for converting pneumatic control pulses into starting and stopping fluid flow. Cartridges are formed by building up laminations, layer by layer, with channels and chambers sealed between capping overlayers. In this way, complex fluidic circuits are formed.
To form a fluidic circuit by conventional fabrication, a layer of an elastic material is sandwiched as a laminate between body layers, and pneumatic and hydraulic channels and chambers are formed in the apposing layers on either side of the elastic layer, such that the pneumatic workings and the hydraulic workings of the cartridge are separated by a diaphragm layer. Diaphragms formed of polyurethane, polyimide, and PDMS have been favorites for this method.
Miniature pump elements, for example, are needed to achieve the fullest benefit of fluidic microcircuitry technologies, which find numerous applications such as in diagnostics and in life sciences more generally. Diaphragm-driven pumps are advantageous because of the absence of mechanical seals and lubricant, and their sanitary features.
Although miniature pumps were generically hinted at by Wilding (for example in U.S. Pat. Nos. 5,304,487 and 5,498,392), the disclosures themselves were not sufficient to enable fluidic microcircuitry pumps and valves. Cited by Wilding was Van Lintel [1988, “A Piezoelectric Micropump Based on Micromachining of Silicon,” Sensors and Actuators, 15:153-167], which relates to silicon-based microelectromechanical (MEMS) structures. However, silicon is known to have a very high Young's modulus (about 100 GPa); therefore a silicon diaphragm pump will generally have a very low compression ratio ε defined by:ε=(ΔV+V0)/V0 where ΔV is the stroke volume and V0 is the deadspace volume, i.e., the volume of fluid that is not displaced from the pumping chamber during an ejection stroke. Thus disadvantageously, these devices may not be self-priming in operation when used with liquids.
Representative art related to siliceous diaphragm pumps includes U.S. Pat. Nos. 5,759,014, 6,390,791 and 7,749,444. Similar issues are seen with the rigid polymeric diaphragm members of U.S. Pat. No. 7,832,429 and more generally where the diaphragm member resists deformation due to mechanical stiffness.
There has been greater interest in elastomeric diaphragm materials because of the higher compression ratio, which offers the advantage of self-priming in fluidic operations, and larger displacement volume. For example, polydimethylsiloxane (PDMS) and silicones may be used as diaphragm materials. Latex rubber and amorphous polyurethanes have also been used. Elastomeric materials that obey Hooke's law have the advantage that the diaphragm returns to its original shape in the relaxed state, but this is advantageous only for some applications, and can be associated with reduced chemical resistance and increased permeability.
Representative art related to microvalves includes U.S. Pat. No. 4,304,257 (the '257 valve), in which a soft, resilient, polyurethane sheet is clamped over flow channels formed in a hard acrylic body. A fluid path between two discontinuous fluid channels is opened and closed by actuating pistons which mechanically flex a part of the sheet. A tenting action on the sheet is associated with valve opening; valve closing is associated with spring return of the resilient sheet to a closed position. The sheet is flexed mechanically between the two positions by a solenoid-operated rod having an embedded attachment to the sheet over the valve seat, such that the sheet contacts the seat when closed and the sheet is pulled into an aperture overlying the valve seat to open the valve.
According to the teachings of U.S. Pat. No. 4,848,722, the '257 valve has several disadvantages. In addition to delicacy of mechanical solenoid operation and need for fine adjustment, the membrane is subjected to great stresses with the risk of permanent stretch (i.e., permanent deformation or pinching past its yield point). By virtue of the concave contact surface for the membrane, the sealing area is maximized, but disadvantageously, a non-zero and significant volume of the valve cavity must be filled before fluid begins to flow.
In expired U.S. Pat. No. 4,848,722 (the '722 valve), a pressure or vacuum source is used to urge a flexible sheet such as biaxially oriented polyethylene terephthalate (BoPET) into a stop-flow position in which apertures formed by the channels (3,4) in the valve seat are closed and an open position in which the apertures are fluidly confluent. The step land (FIG. 9: 62) of the valve seat is contacted by sheet (8) when the valve is closed. The sheet is glued to the pneumatic side of the valve.
U.S. Pat. No. 4,869,282 describes a micromachined valve having a diaphragm layer sandwiched between two rigid layers forming the valve cavity. The diaphragm layer is formed of polyimide and is deflected by an applied pneumatic pressure in a control circuit to close the valve. Diaphragm motion is limited to avoid overstressing the polyimide layer.
Expired U.S. Pat. No. 5,660,370 (the '370 valve) describes a valve (FIG. 1: 1) having flexible diaphragm (2) and flat valve seat formed of a rigid layer in which two holes are formed, each hole defining an opening to a fluidic channel (3,4) in an underlying layer, where the holes are separated by a valve sill. The diaphragm is made of polyurethane or silicone. The valve (5) is opened by pneumatically exercising the diaphragm. To avoid the tendency of the sheet to become stressed beyond its yield point, a flat valve seat is used to minimize the required range of diaphragm motion. This also reduces the deadspace volume of the valve.
A similar structure is seen in U.S. Pat. No. 5,932,799 to YSI Inc., which teaches a fluidic microcircuitry analyzer having a plurality of polyimide layers, preferably KAPTON® film, directly bonded together without adhesives and a flexible pneumatically actuated diaphragm member for controlling fluid flow.
WO Publ. No. 2002/081934 to Micronics, Inc., published Oct. 17, 2002, describes a laminated valve having an elastomeric diaphragm. These valves, which were termed “peanut valves”, admit fluid across the valve sill under negative pressure, and are closed when positively pressurized. Advantageously, the valve cavity is formed with a contoured waist to minimize deadspace volume.
U.S. Pat. No. 7,445,926 to Mathies describes a laminate with a flexible diaphragm layer sandwiched between hard substrates. Pneumatic channels and fluid channels are formed on opposite sides of the diaphragm layer (cf., FIG. 1 of the reference), so that the diaphragm is the active valve member. The diaphragm material disclosed is a 254 micrometer PDMS membrane. The valve body is typically a solid such as glass.
US Pat. Appl. Nos. 2006/0275852 and 2011/0207621 to Montagu describe a fluidic cartridge for biological assays. The cartridge includes a molded body defining flow passages. A latex diaphragm and a canned diaphragm pump are shown (cf., FIG. 5 of the reference). The “rolling elastic diaphragm pump” member (3) is inserted into the cartridge as a pre-formed subassembly and is commercially available (Thomas Pumps, Model 1101 miniature compressor, Sheboygan, Wis. 53081). Valves are mechanically actuated using a stepper motor. Thus the valves have the disadvantage of requiring sensitive and meticulous adjustment for proper operation.
Other elastomeric valve and pump constructs are known. Examples of silicone valve construction include U.S. Pat. Nos. 5,443,890, 6,793,753, 6,951,632 and 8,104,514, all of which illustrate soft lithographic processes (cf., U.S. Pat. Nos. 7,695,683 and 8,104,497) for forming valves and pumps. PDMS may be used to form diaphragms and pump bodies. Latex rubber and amorphous polyurethanes have also been used as diaphragm materials, but chemical resistance may not be sufficient for some applications.
Diaphragm members having toughness, solvent resistance and capable of being shaped into yield-in-place diaphragms have not previously been demonstrated. Advantageously, a solvent-resistant diaphragm that yields to form a pre-shaped diaphragm member has application in pumps and valves used for pumping suspensions of particulates, and for replacing elastomeric diaphragms such as polyurethane which may leak when exposed to caustics, chaeotropes, or solvents, thus permitting use of solvents such as ethanol, formamide and dimethylsulfoxide, e.g., for lowering the operating temperature requirements during PCR. Yield-in-place diaphragms have increased pump stroke ejection volumes, leading to faster circuit response, and improved flow of particulate solutions, such as bead slurries, for example. Although progress has been made, there is a need for improved diaphragm construction of microassay cartridges, and in particular for a process applicable to miniaturized circuit elements. The present invention provides these and related advantages.